Phenethylamide derivatives

ABSTRACT

Phenethylamide derivatives which are n-substituted with talkoxycarbonyl, 5-oxo-2-pyrrolidine carbonyl, phenylsulfonyl or nitrophenylthio and are useful as hypotensive, antipyretic and antiparkinson agents.

United "States Patent [191 Kaiser et al.

[ 1 Jan. 14, 1975 PHENETHYLAMIDE DERIVATIVES Inventors: Ado Kaiser,Neu-Frenkendorf;

Wolfgang Koch, Riehen; Marcel Scheer, Basel; Uwe Wolcke, Bottmingen, allof Switzerland Assignee: Hoifmann-La Roche Inc., Nutley,

Filed: Sept. 13, 1973 Appl. No.: 396,920

Related U.S. Application Data Division of Ser. No. 187,118, Oct. 6,1971, Pat. No. 3,793,342.

U.S. Cl 260/471 C Int. Cl. C07c 125/06 Field of Search 260/471 C [56]References Cited UNITED STATES PATENTS 3,742,022 6/1973 Verbiscar260/471 C Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L.A. Thaxton Attorney, Agent, or FirmSamuel L. Welt; Jon S. Saxe; GeorgeM. Gould [57] ABSTRACT 6 Claims, N0 Drawings 1 PHENETHYLAMIDEDERIVATIVES This is a division of application Ser. No. 187,118, filedOct. 6, 1971, now US. Pat. No. 3,793,342.

SUMMARY OF THE INVENTION In accordance with this invention, it has beendiscovered that compounds of the formula u ca -ca rier:

H wherein R is lower t-alkoxy-carbonyl, -oxo-2pyrrolidinc-carbonyl,phenylsulfonyl,

wherein R is lower t-butoxycarbonyl, 5-oxo-2- pyrrolidinecarbonyl,n-benzyloxycarbonyl-5-oxo- 2-pyrrolidinecarbonyl, phenylsulfonyl andalkylphenylsulfonyl and R is benzyl or by subjecting a compound ofthe'formula:

R 000 H CH NHR" R 000 III amine]; N-(3,4-dihydroxyphenethyl)-5-oxo-L-2-pyrrolidinecarboxyamide;N-(ptoluenesulphonyl dopamine; and N-[(o-nitrophenyl)thio]-dopamine orsalts of these compounds.

DETAILED DESCRIPTION OF THE INVENTION The aforementioned aliphaticgroups can be-straightchain or branched-chain. The lower alkylgroups'preferably contain up to 7 carbon atoms such as, for example,methyl, isopropyl, n-hexyl or n-heptyl. The lower t-alkoxycarbonylgroups preferably contain up to 8 carbon atoms such as, for example, thet-butoxy carbonyl or t-heptyloxycarbonyl group. 7

The compounds of formula I hereinbeforc form salts with bases. Suchsalts include, for example, the disodium, dipotassium and diammoniunisalts.

In accordance with one embodiment of this invention, the boric acidcomplex of a compound of formula I used as the starting material can beprepared asfollows:

A solution of dopamine of the formula H I IV or of a salt thereof istreated with boric acid or a borate salt while maintaining a pH value ofat least about 7.

Borax is preferably used, although other salts of boric acid such as,forexample, the alkali metal metaborates (e.g. sodium metaborate) andalkali metal pent'aborates (e.g. potassium pentaborate) canalso be used.

=Water ispreferably used as the solvent, although mixtures of water withan inert organic solvent suchas, for

example, tetrahydrofuran, dioxan, dimethyl sulphoxide ordimethylformamide can also be used. The treatment is preferably carriedout at a temperature between about 0C. and about C. Thetreatment ispreferably carried out while maintaining a pH value of between about 7and 13; this being expediently effectedby'the addition of an alkalimetal hydroxide such as sodium hydroxide or an organic base such astriethylamine or pyridine.

By treating dopamine or a salt thereof with boric acid or with a boratesalt in the manner described earlier there isobtained a boric acidcomplex-of dopamine'or complex is subsequently reacted with an agentfurnishing the acid residue'R to yield the desired starting material,i.e. a boric acid complex ofa compound of formula I or of a saltthereof. This reaction 'can be carried out under the conditions whichare usualfor acylation reactions. For example, the boric acid complexobtained can be reacted with the corresponding acid halide, preferablywith the chloride or bromide, or-with'the corresponding acid anhydrideor acid azide. Where'R represents a 5-oxo-2-pyrrolidinecarbonyl group,the boric acid complex can be treated with an, activated ester. The acidresidue of the activated ester yields the group R which is to beintroduced. For example, an ester of 5-oxo-2-pyrrolidine-carboxylic acidwith N- hydroxysuccinimide, N-hydroxyphthalimide or pnitrophenol can beused. The reaction medium, the temperature and the pH for theintroduction of the acid residue R are preferably the same as inthe'preparation of the boric acid complex of dopamine.

The preparation of the boric acid complex of a compound of formula I ispreferably effected in situ starting from dopamine. The boric acidcomplex of a compound of formula I obtained is preferably employeddirectly in solution (i.e. without isolation) in the acidic hydrolysisin accordance with the process provided by the invention.

The acidic hydrolysis of the boric acid complex of a compound of formulaI or of a salt thereof in accordance with one embodiment of the processof this invention is preferably carried out in solution. Preferably, abasic aqueous solution prepared in the manner described earlier isadjusted to a pH value of about 1-4 with an acidic agent. The boric acidcomplex is thereby cleaved and the desired compound of formula I isobtained. As acidic agents there are preferably used mineral acids suchas sulfuric acid, hydrochloric acid, phosphoric acid etc., althoughorganic acids such as monoor polybasic alkanecarboxylic acids (e.g.formic acid, acetic acid, trichloroacetic acid, citric acid, tartaricacid and oxalic acid) can also be used. The acidic hydrolysis can becarried out using the same solvents and at the same temperatures as inthe preparation of the boric acid complex of dopamine described earlier.

The acidic hydrolysis of the boric acid complex of a compound of formula1 yields in a particularly simple manner the selectively N-acylated (orN-sulphonylated or N-sulphenylated) compounds of formula I which areunsubstituted at the phenolic hydroxy groups. The phenolic hydroxygroups present in the boric acid complex are protected against attack bythe agent furnishing the acid group R as well as to a large extentagainst oxidation by atmospheric oxygen.

The compounds of formula II used as starting materials in anotherembodiment of the present process can be prepared by reacting3,4-bis(benzyloxy)- phenethylamine or a salt thereof with an agentfurnishing the group R. This reaction can be carried out under theconditions which are usual for acylation re actions. For example,3,4-bis(benzyloxy)- phenethylamine can be reacted with the correspondingacid halide, preferably with the chloride, or with the correspondingacid azide. Where R represents a 5-oxo-2-pyrrolidinecarbonyl orN-benzyloxycarbonyl- 5-oxo-2-pyrrolidinecarbonyl group,3,4-bis(benzyloxy)-phenethylamine can also be reacted with an activatedester. For example, there can be used an ester of5-oxo-2-pyrrolidinecarboxylic acid or of N-benzyloxycarbonyl-S-oxo-2-pyrrolidinecarboxylic acid withN-hydroxysuccinimide, N-hydroxyphthalimide or p-nitrophenol. Thesereactions are preferably carried out in organic solvents such as, forexample, pyridine, tetrahydrofuran, dimethylformamide or dioxan, ifdesired in the presence of a basic agent such as, for example,triethylamine or pyridine. Where R represents a5-oxo-2-pyrrolidinecarbonyl or N-benzyloxycarbonyl-5-oxo-2-pyrrolidinecarbonyl group, 3,4-bis(benzyloxy)-phenethylamine ora salt thereof can also be reacted directly with the correspondingcarboxylic acid or a salt thereof in the presence of a dehydrating agentsuch as, for example, dicyclohexylcarbodiimide or carbonyldiimidazole,if desired in the presence of a basic agent such as triethylamine orpyridine, to give the desired starting materials of formual II.

The debenzylation of'a starting material of formula II can be carriedout, for example, hydrogenolytically with hydrogen and a hydrogenationcatalyst such as platinum, nickel or palladium, if desired inconjunction with a carrier material such as charcoal or barium sulphate.It is preferred to carry out the hydrogenation in an inert solvent; forexample, in a lower alkanol (e.g. ethanol), tetrahydrofuran,dimethylformamide, dimethyl sulfoxide or a lower alkanecarboxylic acid(e.g. acetic acid). The hydrogenation is preferably carried out at atemperature of from about C. to 80C.

Where R represents a -oxo-2-pyrrolidinecarbonyl,N-benzyloxycarbonyl-S-oxo-2-pyrrolidinecarbonyl or p-toluenesulfonylgroup, the debenzylation can also be carried out by treatment withtrifluoroacetic acid at a temperature between about 20C. and the boilingpoint of the mixture.

In the debenzylation of a compound of formula II, anyN-benzyloxycarbonyl-S-oxo-2-pyrrolidinecarbonyl group R which may bepresent is converted into a 5-oxo-2-pyrrolidinecarbonyl group.

The compounds of formula [I] used as starting materials in yet anotherembodiment of the present process can be prepared, for example, byconverting a propionic acid derivative of the general formula R1000 cn-cn -cooa wherein R, is as above by means of a Hofmann acid amidedegradation into a corresponding isocyanate which is subsequentlyconverted into a starting material of formula lll by treatment witht-butanol, if desired in an inert solvent such as tetrahydrofuran,benzene or toluene, at a temperature between 0C. and the boiling pointof the mixture.

The mild basic hydrolysis of a starting material of formula III ispreferably carried out by treating the starting material in water and/ora lower alkanol with an inorganic base such as sodium hydroxide,potassium hydroxide or a quaternary ammonium hydroxide (e.g.tetramethylammonium hydroxide). Generally, it is preferred to use 3-4mol of the base per mol of starting material of formula III. The mildbase hydrolysis is preferably carried out at a temperature between about0C. and 50C.

The compounds of formula I hereinbefore contain an acid group R whichcan be cleaved off under strongly acidic conditions, especially at hightemperatures. This acid-sensitivity applies in particular to the lowertalkoxy-carbonyl groups (e.g. the t-butoxycarbonyl group) as well as tothe nitrophenylthio groups. With respect to the said acid groups R,attention should therefore be paid in the working-up of the product ofthe present process that the product is not strongly acidified orstrongly acidified and heated, because strongly acidic conditions,especially in conjunction with elevated temperatures, can lead to apartial or complete cleaving-off of this group R with consequentialreduction in yield.

The compounds of formula I hereinbefore and their salts arepharmacodynamically active. They are characterized by manifold actionson the nervous system. In particular, they possess hypotensive,antipyretic and anti-Parkinson properties.

The compounds of formula I hereinbefore can be used as medicaments; forexample, in the form of pharmaceutical preparations which contain themin association with a compatible pharmaceutical carrier. This carriercan be an organic or inorganic inert carrier material which is suitablefor enteral or parenteral administration such as, for example, water,gelatin, gum arabic, lactose, starches, magnesium stearate, talc,vegetable oils, polyalkylene glycols, petroleum jelly, etc. Thepharmaceutical preparations can be made up in solid form (e.g. astablets, dragees, suppositories or capsules) or in liquid form (e.g. assolutions, suspensions or emulsions). The preparations may be sterilizedand- /or may contain adjuvants such as preserving, stabilizing, wettingor emulsifying agents, salts for varying the osmotic pressure orbuffers. They can also contain other therapeutically valuablesubstances.

A pharmaceutical preparation in dosage unit form can expediently containabout mg to about 1000 mg of active ingredient.

The amount of active ingredient to be administered per day depends onthe particular case. In general, in the case of oral administration anamount of active ingredient of about 0.1 to about 4 g., especially about1.5 to about 3 g., will be administered. In the case of intravenousadministration, the amount of active ingredient to be administered perday can lie between about 10 mg and about 2 g., especially about 1 g.The administration is expediently effected in individual doses dividedover the day.

The following Examples illustrate the process provided by the invention.In the Examples concentrated aqueous hydrochloric acid designates anaqueous solution containing 37% by weight hydrochloric acid.

EXAMPLE 1 5.6 g of 1-benzyloxycarbonyl-N-[3,4-bis(benzyloxy)-phenethyl]-5-oxo-L-2-pyrrolidinecarboxamide are hydrogenated in thepresence of 2 g of 5% palladium-oncharcoal in 100 ml of absolutemethanol under normal conditions (i.e. at room temperature andatmospheric pressure). The 2.5 g of N-(3,4-dihydroxyphenethyl)-5-oxo-L-2-pyrrolidinecarboxamide which remain behind after filtering offthe catalyst and evaporating the filtrate at 30C./l2 mmHg melt atl85-186C.

EXAMPLE 2 EXAMPLE 3 14.8 g of 0,0-dibenzyl-N-toluenesulfonyldopamine arehydrogenated in the presence of 3 g of 5% palladium-on-charcoal in 300ml of absolute methanol under conditions given in Example l. The N-toluenesulfonyldopamine which is isolated from the hydrogenationsolution melts at l28129C.

EXAMPLE 4 A solution of 3.7 g of 0,0-dibenzyl-dopamine hydrochloride in80 ml of pyridine is treated dropwise at 0C. with a solution of 2.3 g ofp-toluenesulfonyl chloride in 30 ml of absolute dioxan. The mixture isstirred at room temperature for 12 hours, then poured onto ice, madeCongo-acidic with concentrated aqueous hydrochloric acid and extractedwith ethyl acetate. The 0,0- dibenzyl-N-toluenesulfonyldopamine which isobtained from the extract is taken up in diethyl ether and filteredthrough 30 g of Kieselgel. The pure compound melts at 101103C.

EXAMPLE 5 An aqueous, alkaline solution containing the boric acidcomplex of N-t-butoxycarbonyldopamine is made Congo-acidic with 6-Nsulfuric acid, with addition of ice in an argon atmosphere, andextracted with ethyl acetate. The ethyl acetate extract is washedsuccessively with water, saturated sodium bicarbonate solution andsaturated sodium chloride solution, dried over magnesium sulfate andfiltered. The filtrate is evaporated under reduced pressure.N-t-Butoxycarbonyldopamine of melting point l36l37C. is obtained afterrecrystallization from ethyl acetate/petroleum ether mixture.

EXAMPLE 6 58.5 g of dopamine and g of borax are dissolved in 500 ml ofwater in an argon atmosphere. The solution obtained, which contains theboric acid complex of dopamine, is treated with 6-butoxycarbonyl azideprepared from 60 g of t-butoxycarbonyl hydrazide. The pH of the solutionis held between 9.3 and 9.8 by the simultaneous dropwise addition of ca300 ml of ZN'sodium hydroxide. The reaction mixture is stirred at roomtemperature for 15 minutes. The aqueous phase, which contains the boricacid complex of N-t-butoxycarbonyldopamine, is used in the processwithout iso lation of the product.

EXAMPLE 7 An aqueous, alkaline solution containing the boric acidcomplex of N-[(o-nitrophenyl)thiol-dopamine is acidified to pH 2 with6-N aqueous sulfuric acid, with ice-cooling in an argon atmosphere andextracted with ethyl acetate. The ethyl acetate extracts are washed with10% potassium bicarbonate solution and then with saturated sodiumchloride solution, dried over sodium sulfate, filtered and evaporatedunder reduced pressure. 0,0-Nitrophenyldisulfide, which is obtained asthe by-product, crystallizes out from the resulting dark oil. Theremainder of this by-product is separated by chromatography on Kieselgel[eluting agent: toluene:- methanol in the ratio 9:1 (v:v)]. The pureN-[(onitrophenyl)thio]-dopamine which is obtained is a yellow oil.

EXAMPLE 8 A suspension of 20 g of borax in 300 ml of water and 100 ml ofdioxan is treated in an argon atmosphere with 11.7 g of dopaminehydrobromide and 25 ml of 2-N caustic soda. A solution of 10.5 g ofonitrophenylsulfenyl chloride in 25 ml of dioxan is then added dropwisewith stirring at room temperature. The pH of the mixture is held between9.3 and 9.8 by the simultaneous addition of about 30 ml of 2-N sodiumhydroxide. The mixture is subsequently stirred at room temperature for afurther 2 hours. The aqueous solution, which contains the boric acidcomplex of N-[(onitrophenyl)thio]-dopamine,' is used in the processwithout isolation of the product.

EXAMPLE 9 Tablets of the following composition are prepared:

N-Toluenesulfonyl-dopamine 100 mg Lactose 61 mg Maize starch 30 mgPolyvinylpyrrolidone 4 mg Talcum 5 mg Individual weight of one table!Active ingredient content of one tablet EXAMPLE l0 Gelatin capsulescontaining the following ingredien are prepared:

N-(t-Butoxycarbonyl)-dopamine 50 mg Mannitol 98.5 mg Stearic acid 1.5 mg

Individual weight of one capsule Active ingredient content of onecapsule We claim: 1. Compounds ofthe general formula wherein R is lowert-alkoxycarbonyl or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein said compound isN-(t-butoxycarbonyl)-dopamine.

3. A boric acid complex of compounds of the formula in H0 CH CH NHRwherein R' is lower t-alkoxy-carbonyl or pharmaceutically acceptablesalts thereof.

4. The complex of claim 3, wherein R"" is tbutoxycarbonyl.

5. A compound of the formula wherein R is lower t-butoxycarbonyl and Ris benzyl. 6. A compound of the formula R C0O ca om-Nan" R COO whereinR" is lower t-alkoxycarbonyl and R is lower alkyl or phenyl.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 13,860,630

DATED 1 January 14, 1975 INVENTOR(S) I Ado Kaiser, Wolfgang Koch, MarcelScheer and Uwe Wolcke It is certified that error appears in theab0ve-identified patent and that said Letters Patent are herebycorrected as shown below:

Cover page, after [21] Appl. No.: 396,920" insert:

[30] Foreign Application Priority Data October 30, 1970 Switzerland N0.16044/70 Signed and Scalul this thirtieth Day of December 1975 [SEAL]Attest:

2. The compound of claim 1 wherein said compound isN-(t-butoxycarbonyl)-dopamine.
 3. A boric acid complex of compounds ofthe formula
 4. The complex of claim 3, wherein R'''''' ist-butoxycarbonyl.
 5. A compound of the formula
 6. A compound of theformula